Pancreatic ductal adenocarcinoma is an aggressive and deadly disease that is characterized by invasive, metastatic progression and profound resistance to conventional therapeutics. One central player in hallmark pathways important for tumor growth and progression is the AKT kinase. Studies in this laboratory have highlighted differences between AKT1 and AKT2 with regard to their involvement in human cancer and their expression in normal tissues. One important conclusion from recent AKT isoform studies is that AKT1 and AKT2 may have distinct roles in controlling migration and invasion, at least in breast epithelial and carcinoma cells. However, the regulation of different responses by AKT isoforms is largely unknown and may be context dependent. In this proposal, we will establish how responses to different AKT isoforms translate to pancreatic cancer progression. The central hypothesis of this proposal is that AKT cooperates with genetic perturbations mapped within the classical pancreatic tumor progression cascade to facilitate tumor cell proliferation and survival, but that different AKT isoforms may have different roles in regulating pancreatic tumor cell migration and invasiveness. The study of specific AKT isoforms ultimately may elucidate how to suppress tumor progression without adversely affecting other essential cell functions. The specific aims of this proposal are to: 1) Characterize pancreatic-specific transgenic mice with activated Akt for the development of pancreatic lesions and/or potential to cooperate with activated KrasG12D to accelerate pancreatic malignancy and metastasis. The Pdx1 promoter will be utilized to drive tetracycline-regulatable, constitutively active myristoylated (Myr) Akt1 or Akt2. Mice expressing MyrAkt1 will be crossed with Pdx1-Cre-activated KrasG12D mice to evaluate the potential in vivo cooperation between Kras and Akt oncoproteins. Mice expressing MyrAkt2 will be generated and examined histologically, although crosses to generate MyrAkt2;Pdx1-Cre- activated KrasG12D progeny are expected to be beyond the scope of this proposal. 2) Determine the molecular profile of tumors arising in pancreatic-specific transgenic mice with activated Akt1 and in mice with both activated Akt1 and KrasG12D. We will determine if molecular alterations found in pancreatic tumors from mice expressing MyrAkt1 or MyrAkt1;KrasG12D recapitulate other molecular events important in human pancreatic cancers. Pancreatic tumors also will be examined for recurrent somatic genetic changes that may cooperate oncogenically with activated Akt1. These investigations will enhance our understanding of the role of AKT1 and AKT2 in the molecular pathogenesis of pancreatic cancer and will clarify how different AKT isoforms cooperate with known perturbations in the classical progression pathway to promote pancreatic cancer. The long-range goal, given that AKT is an integral signaling protein in several pathways important for tumor vitality, is to define pathway-specific targets that may lead to improved strategies for pancreatic cancer prevention and/or therapy. PUBLIC HEALTH RELEVANCE: In this proposal, genetically defined mouse models will be used to ascertain whether specific AKT isoforms have different roles in aspects of pancreatic tumor proliferation and/or invasion/metastasis. Tumors arising in these mice will be examined for other molecular alterations that are known to be important for human pancreatic tumor development. These studies are expected to provide insights regarding the pathogenetic implications of AKT perturbations in human pancreatic cancer, and define key molecules in the AKT signaling pathway that may be therapeutically targeted to inhibit refractory or recurrent pancreatic cancer.